Novel Oral Pharmaceutical Suspension of Cefdinir Crystal

ABSTRACT

The present invention relates to a novel oral pharmaceutical suspension of Cefdinir crystal. More specifically, the present invention relates to a novel kit for preparation of an oral pharmaceutical suspension containing crystal form C Cefdinir.

REFERENCE TO PRIOR APPLICATION

This application is a divisional application of U.S. application Ser.No. 11/289,333, filed Nov. 30, 2004, which claims priority to U.S.Provisional Application 60/631,628, filed Nov. 30, 2004, both of whichare herein incorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel oral pharmaceutical suspensionof crystalline Cefdinir. More specifically, the present inventionrelates to a novel kit for preparation of an oral pharmaceuticalsuspension containing crystal form C Cefdinir.

BACKGROUND ART

7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), known as Cefdinir, is a cephalosporin antibiotichaving high antibiotic activity and broad antibacterial spectrum.Cefdinir was first disclosed in U.S. Pat. No. 4,559,334, which isincorporated herein by reference.

To date, two crystal forms of Cefdinir have been observed and preparedin view of suitability for a pharmaceutical product and ease forhandling. One crystal form of Cefdinir (hereinafter referred to as“crystal form A”) has been disclosed in, for example, U.S. Pat. No.4,935,507, incorporated herein by reference, which has been widely usedas an oral pharmaceutical suspension form.

Another crystal form of Cefdinir (monohydrate, also referred to as“crystal form B”) including its method of preparation has been disclosedin JP Patent application No. 62-206199 found in the file of EP0304019,which is incorporated herein by reference. Recently, crystal form B hasalso been described in US 2003/0204082 A1. However, crystal form B ofCefdinir has not been used to form oral suspensions.

SUMMARY OF THE INVENTION

In the present application, the present inventors have studied thephysicochemical properties of the lower hydrates of Cefdinir, andestablished the present invention based on the novel knowledge gainedfrom these studies.

Specifically, the present inventors have found that crystal form A ofCefdinir exists in an aggregate of small crystals, whereas the lowerhydrates of Cefdinir, such as the monohydrate sometimes called crystalform B, exist in the shape of needles. Furthermore, the presentinventors have found that the lower hydrates of Cefdinir transform toanother hydrate having 1.5 to two or more waters of hydration per moleof Cefdinir in high moisture condition or aqueous solvent and exist asanother crystal form, a higher hydrate. That is, in high moisturecondition or aqueous media, the lower hydrates of Cefdinir transform toa higher hydrate (also referred to as “crystal form C”) which may bepresent as the sesquihydrate, dihydrate, trihydrate, trihemyhydrate,tetrahydrate, etc. or mixtures thereof. The sedimentation rate ofcrystal form C in aqueous solvent is lower than that of crystal form A,and dispersibility of crystal form C in aqueous solvent is higher thanthat of crystal form A. This phenomenon is most likely due to the shapeof the lower hydrate crystal and the transformation of the lower hydratecrystal to crystal form C in aqueous solvent. The above-describedproperties of the lower hydrate and form C found by the presentinventors make it easier for people to take an oral pharmaceuticalsuspension containing Cefdinir and allow for long storage of an oralpharmaceutical suspension containing Cefdinir.

In one aspect, the invention provides a kit for preparation of an oralpharmaceutical suspension of crystal form C Cefdinir, wherein said kitcomprises: (a) a composition comprising a lower hydrate of Cefdinirwithin a first container; and (b) a label or a written materialindicating that said composition can be used to be admixed withpharmaceutically acceptable aqueous carrier, wherein said compositioncan be admixed with said carrier to form an oral pharmaceuticalsuspension of crystal form C Cefdinir.

In other aspect, the present invention provides an oral pharmaceuticalsuspension comprising crystal form C Cefdinir and pharmaceuticallyacceptable aqueous carrier.

In other aspect, the present invention provides a method for preparingan oral pharmaceutical suspension comprising crystal form C Cefdinir,comprising admixing composition containing a lower hydrate of Cefdinirwith a pharmaceutically acceptable aqueous carrier.

In other aspect, the present invention provides a crystal form CCefdinir.

In other aspect, the present invention provides a pharmaceuticalcomposition comprising crystal form C Cefdinir.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows SEM micrographs of crystal form A and the monohydrate ofCefdinir.

FIG. 2 shows moisture adsorption/desorption isotherm at 25° C. ofCefdinir monohydrate.

FIG. 3 shows powder X-ray diffraction pattern of Cefdinir monohydrate atvarious relative humidities.

FIG. 4 shows powder X-ray diffraction pattern of Cefdinir monohydrateafter stirring in water for 5 minutes.

FIG. 5 shows dispersion state of crystal form A of Cefdinir and Cefdinirmonohydrate.

FIG. 6 shows change of transmittance of suspensions prepared withcrystal form A of Cefdinir and Cefdinir monohydrate.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The process for preparing Cefdinir is known in the art and has beendisclosed in U.S. Pat. No. 4,559,334, incorporated herein.

One process for preparing Cefdinir monohydrate is known in the art anddisclosed in JP Patent application No. 62-206199. Another process hasbeen disclosed in US 2003/0204082 A1. The monohydrate obtained maycontain some crystal form A.

The term “lower hydrates” includes all hydrated forms of Cefdinir whichconvert in the presence of water or water moisture into higher hydrates(crystal form C) such as the sesquihydrate and trihemihydrate. Oneparticularly preferred lower hydrate is the monohydrate, sometimescalled crystal form B. Lower hydrates may contain up to about 1.25 molesof water per mole of Cefdinir. There is no minimum amount of water whichthe lower hydrates must contain except that it must be greater thanzero. Generally, the lower hydrates will contain from about 0.5 to 1.25moles of water per mole of Cefdinir, preferably about 1.0. The lowerhydrates may contain a mixture of hydrated forms and also may containsome form A, from 0 to 50% by weight.

In one embodiment, the kit of the present invention comprises acomposition comprising Cefdinir lower hydrate within a first containerand a label or a written material indicating that said composition canbe admixed with pharmaceutically acceptable aqueous carrier, whereinsaid composition can be admixed with said carrier to form an oralpharmaceutical suspension of crystal form C Cefdinir. Preferably, thelower hydrate is the monohydrate. However, so far as oral suspensioncontaining crystal form C Cefdinir can be formed, other crystal formthan the lower hydrates of Cefdinir may be used in the composition.Crystal form C in the oral suspension includes any higher hydrate formsuch as sesquihydrate, dihydrate, trihydrate, trihemyhydrate andtetrahydrate, so far as it is converted from the lower hydrate in theoral suspension. Examples of the oral suspension of the presentinvention includes, but are not limited to, the oral suspension whichmainly contains Cefdinir trihemihydrate containing 3.5 moles of waterper mole of Cefdinir. The crystal lattice structure of trihemihydratecontains about 14 moles of water per the unit cell. About 10 moles ofwater are found in the crystal channels. However, the oral suspensionmay contain some other higher hydrates of Cefdinir such assesquihydrate, dihydrate, trihydrate and tetrahydrate.

In one embodiment, the kit further comprises pharmaceutically acceptableaqueous carrier within a second container, wherein said carrier can beadmixed with said composition to form an oral pharmaceutical suspensionof said crystal form C. In another embodiment, the kit further comprisesa container used for admixing said composition with saidpharmaceutically acceptable aqueous carrier to form an oralpharmaceutical suspension of said crystal form C.

Preferably, said composition comprising Cefdinir lower hydrate isadmixed with said pharmaceutically acceptable aqueous carrier to form anoral pharmaceutical suspension of said crystal form C immediately beforesaid oral pharmaceutical suspension is used. Alternatively, multipledoses of said composition comprising Cefdinir lower hydrate may beadmixed with said pharmaceutically acceptable aqueous carrier at onceand may be preserved for using at later.

The oral pharmaceutical suspension of the present invention comprisescrystal form C Cefdinir and pharmaceutically acceptable aqueous carrier.The oral pharmaceutical suspension of the present invention can beprepared by admixing Cefdinir lower hydrate with pharmaceuticallyacceptable aqueous carriers.

The pharmaceutically acceptable aqueous carrier to be used in thepresent invention includes water and other diluent known in the artsuitable for preparing oral pharmaceutical suspension. Preferably, thepharmaceutically acceptable aqueous carrier is water.

The oral pharmaceutical suspension of the present invention may include,if necessary, pharmaceutically acceptable additives including auxiliarysubstances, stabilizing agents, suspending agents, surface tensionmodifiers, viscosity modifiers, colorants, preservatives, flavoringagents and other commonly used additives such as lactose, citric acid,tartaric acid, stearic acid, magnesium stearate, sucrose, and the like.In one embodiment, such additive may be included in the compositioncomprising Cefdinir lower hydrate in the kit of the present invention,and in other embodiment, such additive may be included in thepharmaceutically acceptable aqueous carrier in the kit of the presentinvention. In one embodiment, the composition comprised in the kit ofthe present invention contains about 125 mg crystal form of Cefdinir andabout 3.0 g sucrose, and the composition can be admixed with 5 ml wateras a pharmaceutically acceptable carrier to form an oral pharmaceuticalsuspension of crystal form C Cefdinir.

The container to be used in the present invention includes, but is notlimited, bottle, vial, paper bag, test tube, and pharmaceuticallyacceptable container known in the art. The container may be formed fromone or more materials such as plastic, glass or paper.

The amount of Cefdinir to be contained in the oral pharmaceuticalsuspension of the present invention may vary and depend upon the age,conditions of the patient, a kind of diseases, etc. In general, amountsbetween 1 mg and about 4,000 mg or even more per day may be administeredto a patient. For example, an average single dose of about 10-1,000 mg,preferably about 50-500 mg, more preferably about 100-250 mg of Cefdinirmay be used in treating diseases infected by pathogenic microorganisms.

EXAMPLE

The monohydrate was prepared as follows: Cefdinir (20.0 g) was added towater (200 ml) and the mixture was adjusted to pH 6.0 with saturatedsodium bicarbonate aqueous solution. The resultant solution wassubjected to a column chromatography on activated charcoal and elutedwith 20% aqueous acetone. Fractions were combined and then concentratedto 200 ml. This solution was adjusted to pH 2.2 at 15° C. with 10%hydrochloric acid and stirred at 0° C. for 30 minutes. The resultantcrystals were collected by filtration, washed with water and dried togive crystals of Cefdinir monohydrate. The present inventorsinvestigated physicochemical properties for Cefdinir monohydrate andcrystal form A. The results are described below.

1. Scanning Electron Microscopy (SEM)

SEM micrographs (HITACHI S-800) of form A and the monohydrate are shownin FIG. 1. It is clear from the figures that form A is an aggregate ofsmall crystals, whereas the monohydrate is a needle shape.

2. Physical Properties

The present inventors investigate the interconversion of the forms asfollows.

2-1. Moisture Adsorption/Desorption Isotherm

The moisture adsorption/desorption isotherms of the monohydrate weremeasured in relative humidities of 5 to 95% at 2520 C. by microbalancemethod (VTI MB-300W (Microbalance) and MKA-510 (Kyoto electronics MFG,LTD.)). The obtained moisture adsorption/desorption isotherm is shown inFIG. 2. The water increased to the content corresponding to higherhydrate form at the relative humidity of more than 70%, and totrihydrate at the higher relative humidity such as 95%. To confirm thecrystal form at each relative humidity, the powder X-ray diffraction(PXRD) patterns were measured at the each controlled relative humidity(10, 75, and 95% RH) (Rigaku RINT TTR2 and Rigaku HUMIDITY GENERATORHUM-1). The obtained PXRD patterns are shown in FIG. 3. It was confirmthat the obtained PXRD patterns were different from that of intactsample, that is, the PXRD pattern of the monohydrate measure at nocontrolled relative humidity. From these results, it was considered thatthe monohydrate transformed to another higher hydrate (crystal form C)at high relative humidity, and crystal form C keeps 1.5 or moremolecules of crystalline waters.

2-2. Solvent Medium Transformation

Form A and the monohydrate were suspended in water or ethanol (99.5) atroom temperature, and the powder X-ray diffraction (PXRD) patterns ofthe residual solid materials were measured (Bruker AXS D8 Discover withGADDS). FIG. 4 shows PXRD pattern of the residual solid obtained fromthe monohydrate after 5 minutes stirring in an aqueous suspension, andit was confirmed that the obtained pattern corresponded to that ofanother hydrate keeping much amount of molecules of crystalline water.Therefore, it was concluded that the crystalline change from monohydrateto crystal form C was occurred in an aqueous suspension.

On the other hand, form A showed no crystalline conversion to othercrystal form in aqueous and ethanol suspensions.

3. Dispersibility Comparison Assay

The dispersibility of two crystal forms of Cefdinir was compared byevaluating sedimentation rates of two crystal forms. The evaluatingsedimentation rate was conducted by using two methods as follow.

3-1. Method 1

About 1250 mg of crystal form A or the monohydrate were dispersed in 50mL of water (125 mg/5 mL), and the suspensions were vigorously shaken byhand. Then, the appearances of contents were observed in a test tube(about sediments and lumps). The pictures of suspension states weretaken with time. As shown in FIG. 5, the dispersion state of thesuspension of the monohydrate was better than that of form A, and thesedimentation rate of the monohydrate was slower than that of form A.

3-2. Method 2

5 mg of crystal form A or the monohydrate were dispersed in 10 mL ofwater (sample concentration: 0.5 mg/mL), and the suspensions werevigorously shaken. Then, the dispersed suspensions were transferred inthe cell for UV measurement, and changes of the transmittances at 650 nmwere measured. As shown in FIG. 6, the transmittance of suspensionprepared with form A showed the faster increase than that of themonohydrate, indicating that form A sank down faster than themonohydrate in the suspension. This result was corresponding to theobservation result of dispersion rate.

The suspension properties of form A can be improved by grinding,however, this adds an additional step which is not necessary with thelower hydrates, such as the monohydrate.

1. A kit for preparation of an oral pharmaceutical suspension of crystalform C of Cefdinir, wherein said kit comprises: (a) a compositioncomprising Cefdinir within a first container; and (b) a label or awritten material indicating that said composition is admixed withpharmaceutically acceptable aqueous carrier prior to administration,wherein said composition when admixed with said carrier forms an oralpharmaceutical suspension of crystal form C of Cefdinir.
 2. A kit forpreparation of an oral pharmaceutical suspension of crystal form C ofCefdinir, wherein said kit comprises: (a) a composition comprising alower hydrate of Cefdinir within a first container; and (b) a label or awritten material indicating that said composition is admixed withpharmaceutically acceptable aqueous carrier prior to administration,wherein said composition when admixed with said carrier forms an oralpharmaceutical suspension of crystal form C of Cefdinir.
 3. The kit ofclaim 2, wherein the lower hydrate of Cefdinir is monohydrate.
 4. Thekit of claim 1 wherein said kit further comprises (c) pharmaceuticallyacceptable aqueous carrier within a second container.
 5. The kit ofclaim 1 wherein said kit further comprises (d) a container used foradmixing said composition with said pharmaceutically acceptable carrierto form an oral pharmaceutical suspension of said crystal form C.
 6. Thekit of claim 1 wherein the pharmaceutically acceptable carrier is water.7. The kit of claim 1, wherein said Cefdinir is admixed with apharmaceutically acceptable additive or mixture of additives.
 8. The kitof claim 2, wherein the lower hydrate of Cefdinir is admixed with apharmaceutically acceptable additive or mixture of additives.
 9. Amethod for preparing an oral pharmaceutical suspension comprisingcrystal form C of Cefdinir, comprising admixing composition containingthe lower hydrate of Cefdinir with a pharmaceutically acceptable aqueouscarrier.
 10. The method of claim 9, wherein the lower hydrate ofCefdinir is monohydrate.